Asthma is a common disease with a complex etiology that includes both genetic and environmental contributions. The Childhood Origins of ASThma (COAST) study is a birth cohort study of high risk children designed to elucidate the relative roles of genes and environment on the developing immune system and subsequent risk for asthma and allergy. During the first 6 years of this study many important findings emerged that provide the focus of this renewal application. In particular, symptomatic rhinovirus (RV) infection in the first year was the most significant predictor of subsequent wheezing illnesses, and the relationship between IFN-gamma responses and wheezing at age 3 differed between boys and girls. More recently we have shown that wheezing with RV infection in the first year is a significant predictor of wheezing at age 5 (p = 0.00047) and asthma at age 6 (p = 0.000095) and mean IFN-gamma responses differ significantly between boys and girls at age 5 (p = 0.0004). We have further identified gene-environment interactions with both RV illness in the first year and with child's sex that influence immune responsiveness and the development of asthma and allergic phenotypes. In this application, we propose to further investigate the role of genes in RV pathways and asses their function (Aim 1) and to further explore potential mechanisms for the observed sex differences in IFN-gamma responses at age 9 (pre-puberty) and age 14 (peripuberty) (Aim 2). Lastly, we propose to study micro(mi)RNA populations in human bronchial epithelial (BE) cells before and after infection with RV, and to examine polymorphisms in the differentially expressed miRNA genes and their targets (Aim 3). All genetic associations detected in the COAST children will be replicated in children participating in the Tucson Infant Immune Study, another birth cohort. Elucidating the mechanisms for these effects could suggest novel therapies or prevention strategies for at-risk children and impact our understanding of the pathogenesis of this common disease.